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SummaryCytoplasmic mislocalization and aggregation of the RNA-binding protein TDP-43 is a pathological hallmark of the motor neuron (MN) disease amyotrophic lateral sclerosis (ALS). Furthermore, while mutations in theTARDBPgene (encoding TDP-43) have been associated with ALS, the pathogenic consequences of these mutations remain poorly understood. Using CRISPR/Cas9, we engineered two homozygous knock-in iPSC lines carrying mutations inTARDBPencoding TDP-43A382Tand TDP-43G348C, two common yet understudied ALS TDP-43 variants. MNs differentiated from knock-in iPSCs had normal viability and displayed no significant changes in TDP-43 subcellular localization, phosphorylation, solubility, or aggregation compared with isogenic control MNs. However, our results highlight synaptic impairments in both TDP-43A382Tand TDP-43G348CMN cultures, as reflected in synapse abnormalities and alterations in spontaneous neuronal activity. Collectively, our findings argue that MN dysfunction precedes the occurrence of TDP-43 pathology and neurodegeneration in ALS, and further implicates synaptic and excitability defects in the pathobiology of this disease.HighlightsMNs differentiated from knock-in iPSCs do not display a neurodegenerative phenotype.Mutant MNs do not show TDP-43 pathology.TDP-43 variants lead to a progressive decline in spontaneous neuronal activity.Functional impairments are accompanied by abnormal synaptic marker expression.eTOC blurbUsing CRISPR/Cas9-edited iPSCs, Lépine et al. demonstrate that ALS TDP-43 variants (TDP-43A382Tand TDP43G348C) lead to alterations in spontaneous neuronal activity and synaptic abnormalities in the absence of TDP-43 mislocalization, aggregation, or neurodegeneration. These findings imply that TDP-43 pathology is not required to induce MN dysfunction and support the presence of early synaptic impairments prior to MN loss in ALS.

BackgroundArchitectural distortion (AD) is a common imaging manifestation of breast cancer, but is also seen in benign lesions. This study aimed to construct deep learning models using mask regional convolutional neural network (Mask-RCNN) for AD identification in full-field digital mammography (FFDM) and evaluate the performance of models for malignant AD diagnosis.MethodsThis retrospective diagnostic study was conducted at the Second Affiliated Hospital of Guangzhou University of Chinese Medicine between January 2011 and December 2020. Patients with AD in the breast in FFDM were included. Machine learning models for AD identification were developed using the Mask RCNN method. Receiver operating characteristics (ROC) curves, their areas under the curve (AUCs), and recall/sensitivity were used to evaluate the models. Models with the highest AUCs were selected for malignant AD diagnosis.ResultsA total of 349 AD patients (190 with malignant AD) were enrolled. EfficientNetV2, EfficientNetV1, ResNext, and ResNet were developed for AD identification, with AUCs of 0.89, 0.87, 0.81 and 0.79. The AUC of EfficientNetV2 was significantly higher than EfficientNetV1 (0.89 vs. 0.78, P=0.001) for malignant AD diagnosis, and the recall/sensitivity of the EfficientNetV2 model was 0.93.ConclusionThe Mask-RCNN-based EfficientNetV2 model has a good diagnostic value for malignant AD.

Osteonecrosis of the femoral head (ONFH) is a potentially debilitating condition, often requiring total hip arthroplasty (THA). Patients on hemodialysis (HD) are at increased risk for complications after THA for osteoarthritis, however there is limited information on outcomes of THA for ONFH in patients on HD. With increasing prevalence of chronic kidney disease (CKD) requiring HD, studies are needed to characterize the risk of complications in these patients. Therefore, the purpose of this study was to evaluate HD as a potential risk factor for complication after THA in patients with ONFH on HD.Patients on HD with ONFH who underwent THA with at least 2 years of follow-up were identified using a combination of ICD-9 and CPT codes in a national insurance database. A 10:1 matched control cohort of patients with ONFH not on HD was created for comparison. A logistic regression analysis was used to evaluate rates of death, hospital readmission, emergency room (ER) visit, infection, revision, and dislocation between cohorts. Differences in hospital charges, reimbursement, and length of stay between the two groups were also assessed.One thousand one hundred thirty-seven patients on HD who underwent THA for ONFH were compared to a matched control cohort of 11,182 non-HD patients who underwent THA for ONFH. Patients on HD experienced higher rates of death (HD 4.1%, non-HD 0.9%; odds ratio [OR] 3.35, p0.01), hospital readmission (HD 16.1%, non-HD 5.9%; OR 2.69, p0.01) and ER visit (HD 10.4%, non-HD 7.4% OR 1.5, p0.01). Hemodialysis was not associated with higher risk of infection, revision, or dislocation, but was associated with significantly higher charges (p0.01), reimbursement (p0.01), and hospital length of stay (p0.01).While patients on HD do not have increased risk of implant-related complications, they are at increased risk of developing medical complications following THA for ONFH and subsequently may require more resources. Orthopedic surgeons and nephrologists should be cognizant of the increased risk in this population to provide appropriate preoperative counseling and enhanced perioperative medical management.Therapeutic Level III.

Osteonecrosis of the femoral head (ONFH) is a potentially debilitating condition, often requiring total hip arthroplasty (THA). Patients with solid organ transplant (SOT) are at increased risk of postoperative complications after THA for osteoarthritis. The objective of the present study is to evaluate SOT as a potential risk factor for complication after THA for ONFH.This is a retrospective study that identified patients with SOT who underwent THA for ONFH from 2005 to 2014 in a national insurance database and compared them to 5:1 matched controls without transplant. Subgroup analyses of patients with renal transplant (RT) and those with non-RT were also analyzed. A logistic regression analysis was used to compare rates of mortality, hospital readmission, emergency room (ER) visits, infection, revision, and dislocation while controlling for confounders. Differences in hospital charges, reimbursement, and length of stay (LOS) were also compared.996 patients with SOT who underwent THA were identified and compared to 4,980 controls. SOT patients experienced no increased risk of early postoperative complications compared to controls. Solid organ transplant was associated with higher resource utilization and LOS. Renal transplant patients were found to have significantly higher risk of hospital readmission at 30 days (odds ratio [OR] 1.77; p = 0.001) and 90 days (OR 1.62; p0.001) and hospital LOS (p0.001), but had lower risk of infection (OR 0.65; p = 0.030). Non-RT patients had higher rate of ER visits at 30 days (OR 2.26; p = 0.004) but lower rates of all-cause revision (OR 0.22; p = 0.043).Patients with history of SOT undergoing THA for ONFH utilize more hospital resources with longer LOS and greater risk of readmission but are not necessarily at an increased risk of early postoperative complications.

We present a large catalogue of molecular clouds with accurate distance estimates in the southern sky. Based on the three-dimensional (3D) dust extinction map and the best-fit extinction and distance information of over 17 million stars presented in Guo et al., we have identified 250 dust/molecular clouds in the southern sky using a hierarchical structure identification algorithm. Amongst them, 71 clouds locating at high Galactic latitudes ($b < -10^\circ$). We have estimated the distances to the clouds by fitting the extinction versus distance profiles of the lines of sight overlapping with the clouds using a simple Gaussian dust distribution model. The typical uncertainties of the distances are less than 7 per$\,$cent. We also provide the physical properties of the individual clouds, including the linear radius, mass and surface mass density., 11 pages, 10 figures, 2 tables, accepted for publication in MNRAS

Seawater intrusion and drinking-water fluorosis are frequently documented along coastal plains. Groundwater is characterized by high OH−, Na+, total dissolved solids, and low Ca2+ because of seawater intrusion, and such conditions favor sediment fluoride-leaching and fluorosis. But the geological process of seawater intrusion has not been noticed when high-fluoride groundwater along coastal areas is discussed. The groundwater and sediments in a typical seawater intrusion and fluorosis area are gained, and fluoride-leaching simulation experiments are performed. Sediment fluoride levels are equal to or lower than average sediment fluoride levels in China and Shandong province, but strong fluoride-leaching in aquifers is observed. Compared with the supplied water from the non-intruded neighboring area, the local groundwater has higher fluoride levels, together with higher pH, total dissolved solids, HCO3−, Cl−, Br−, SO42−, Na+, K+, and low Ca2+ because of seawater intrusion. Aquifer sediment fluoride-leaching ability increases with an increase in seawater (brine water) mixing ratios, and NaCl or NaHCO3 levels, but with a decrease in CaCl2 levels. This directly confirms that seawater (brine water) intrusion promotes sediment fluoride-leaching, and the high pH, Na+, HCO3−, and low Ca2+ levels caused by seawater intrusion are responsible for the high-fluoride groundwater along coastal plains.

Oral potentially malignant disorders (OPMDs) are a heterogeneous group of oral lesions with a variable risk of malignant transformation to oral squamous cell carcinoma. The current OPMDs malignant transformation screening depends on conventional oral examination (COE) and is confirmed by biopsy and histologic examination. However, early malignant lesions with subtle mucosal changes are easily unnoticed by COE based on visual inspection and palpation. Optical techniques have been used to determine the biological structure, composition, and function of cells and tissues noninvasively by analyzing the changes in their optical properties. The oral epithelium and stroma undergo persistent structural, functional, and biochemical alterations during malignant transformation, leading to variations in optical tissue properties; optical techniques are thus powerful tools for detecting OPMDs malignant transformation. The optical imaging methods already used to detect OPMDs malignant transformation in vivo include autofluorescence imaging, narrowband imaging, confocal reflectance microscopy, and optical coherence tomography. They exhibit advantages over COE in detecting biochemical or morphologic changes at the molecular or cellular level in vivo; however, limitations also exist. This article comprehensively reviews the various real-time in vivo optical imaging methods used in the adjunctive diagnosis of OPMDs malignant transformation. We focus on the principles of these techniques, review their clinical application, and compare and summarize their advantages and disadvantages. Finally, we conclude with a discussion of current challenges and future directions of this field.

Low in dietary ω3 polyunsaturated fatty acid (PUFA) consumption has been associated with increased incidence of cancers. Many basic and clinical studies have been conducted over the last several decades. We previously reviewed multi-targeted therapy of cancer by omega-3 fatty acids in 2008, and since hundreds of new clinical trials are being conducted to validate the effectiveness of ω3 PUFA in cancer therapy. Because of the availability of such large amount of clinical trial data, in this update we summarize clinical data, sort out trials that show promising results, and discuss potential mechanism(s) responsible for the clinical outcomes. It appears that ω3 PUFA mainly affects cancer-associated symptoms, namely cachexia, inflammation, neuropathy, post operative complications and quality of life. Mechanisms responsible for these effects are possible regulation of skeletal muscle protein turnover, inflammatory response and neuron cell survive by ω3 PUFA.

In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy or in combination with pembrolizumab.Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1.Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs-the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs-the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy.Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.

We present high-resolution maps of the dust reddening in the Magellanic Clouds (MCs). The maps cover the Large and Small Magellanic Cloud (LMC and SMC) area and have a spatial angular resolution between $\sim$ 26 arcsec and 55 arcmin. Based on the data from the optical and near-infrared (IR) photometric surveys, including the Gaia Survey, the SkyMapper Southern Survey (SMSS), the Survey of the Magellanic Stellar History (SMASH), the Two Micron All Sky Survey (2MASS) and the near-infrared $YJK_{\rm{S}}$ VISTA survey of the Magellanic Clouds system (VMC), we have obtained multi-band photometric stellar samples containing over 6 million stars in the LMC and SMC area. Based on the measurements of the proper motions and parallaxes of the individual stars from Gaia Early Data Release 3 (Gaia EDR3), we have built clean samples that contain stars from the LMC, SMC and Milky Way (MW), respectively. We apply the spectral energy distribution (SED) fitting to the individual sample stars to estimate their reddening values. As a result, we have derived the best-fitting reddening values of ~ 1.9 million stars in the LMC, 1.5 million stars in the SMC and 0.6 million stars in the MW, which are used to construct dust reddening maps in the MCs. Our maps are consistent with those from the literature. The resultant high-resolution dust maps in the MCs are not only important tools for reddening correction of sources in the MCs, but also fundamental for the studies of the distribution and properties of dust in the two galaxies., Comment: 13 pages, 14 figures, accepted for publication in MNRAS

Fatty acid desaturase (FADS) generates double bond at a certain position of the corresponding polyunsaturated fatty acids (PUFAs) with high selectivity, the enzyme activity and PUFAs products of which are essential to biological systems and are associated with a variety of physiological diseases. Little is known about the structure of FADSs and their amino acid residues related to catalytic activities. Identifying key residues of Micromonas pusilla delta 6 desaturase (MpFADS6) provides a point of departure for a better understanding of desaturation. In this study, conserved amino acids were anchored through gene consensus analysis, thereby generating corresponding variants by site-directed mutagenesis. To achieve stable and high-efficiency expression of MpFADS6 and its variants in Saccharomyces cerevisiae, the key points of induced expression were optimized. The contribution of conserved residues to the function of enzyme was determined by analyzing enzyme activity of the variants. Molecular modeling indicated that these residues are essential to catalytic activities, or substrate binding. Mutants MpFADS6[Q409R] and MpFADS6[M242P] abolished desaturation, while MpFADS6[F419V] and MpFADS6[A374Q] significantly reduced catalytic activities. Given that certain residues have been identified to have a significant impact on MpFADS6 activities, it is put forward that histidine-conserved region III of FADS6 is related to electronic transfer during desaturation, while histidine-conserved regions I and II are related to desaturation. These findings provide new insights and methods to determine the structure, mechanism and directed transformation of membrane-bound desaturases.

Interferometers are crucial for precision measurements, including gravitational waves, laser ranging, radar, and imaging. The phase sensitivity, the core parameter, can be quantum-enhanced to break the standard quantum limit (SQL) using quantum states. However, quantum states are highly fragile and quickly degrade with losses. We design and demonstrate a quantum interferometer utilizing a beam splitter with a variable splitting ratio to protect the quantum resource against environmental impacts. The optimal phase sensitivity can reach the quantum Cram\'{e}r-Rao bound of the system. This quantum interferometer can greatly reduce the quantum source requirements in quantum measurements. In theory, with a 66.6% loss rate, the sensitivity can break the SQL using only a 6.0 dB squeezed quantum resource with the current interferometer rather than a 24 dB squeezed quantum resource with a conventional squeezing-vacuum-injected Mach-Zehnder interferometer. In experiments, when using a 2.0 dB squeezed vacuum state, the sensitivity enhancement remains at ~1.6 dB via optimizing the first splitting ratio when the loss rate changes from 0% to 90%, indicating that the quantum resource is excellently protected with the existence of losses in practical applications. This strategy could open a way to retain quantum advantages for quantum information processing and quantum precision measurement in lossy environments., Comment: 6 pages, 4 figures

Whey is a by-product of cheese, casein, and yogurt manufacture. It contains a mixture of proteins that need to be isolated and purified to fully exploit their nutritional and functional characteristics. Protein-enriched fractions and highly purified proteins derived from whey have led to the production of valuable ingredients for many important food and pharmaceutical applications. This article provides a review on the separation principles behind both the commercial and emerging techniques used for whey protein fractionation, as well as the efficacy and limitations of these techniques in isolating and purifying individual whey proteins. The fractionation of whey proteins has mainly been achieved at commercial scale using membrane filtration, resin-based chromatography, and the integration of multiple technologies (e.g., precipitation, membrane filtration, and chromatography). Electromembrane separation and membrane chromatography are two main emerging techniques that have been developed substantially in recent years. Other new techniques such as aqueous two-phase separation and magnetic fishing are also discussed, but only a limited number of studies have reported their application in whey protein fractionation. This review offers useful insights into research directions and technology screening for academic researchers and dairy processors for the production of whey protein fractions with desired nutritional and functional properties.

Triglyceride (TG) metabolism is highly regulated by angiopoietin-like protein (ANGPTL) family members [Y. Q. Chen et al. , J. Lipid Res. 61 , 1203–1220 (2020)]. During feeding, ANGPTL8 forms complexes with the fibrinogen-like domain-containing protein ANGPTL4 in adipose tissue to decrease ANGPTL3/8- and ANGPTL4-mediated lipoprotein lipase (LPL)-inhibitory activity and promote TG hydrolysis and fatty acid (FA) uptake. The ANGPTL4/8 complex, however, tightly binds LPL and partially inhibits it in vitro. To try to reconcile the in vivo and in vitro data on ANGPTL4/8, we aimed to find novel binding partners of ANGPTL4/8. To that end, we performed pulldown experiments and found that ANGPTL4/8 bound both tissue plasminogen activator (tPA) and plasminogen, the precursor of the fibrinolytic enzyme plasmin. Remarkably, ANGPTL4/8 enhanced tPA activation of plasminogen to generate plasmin in a manner like that observed with fibrin, while minimal plasmin generation was observed with ANGPTL4 alone. The addition of tPA and plasminogen to LPL-bound ANGPTL4/8 caused rapid, complete ANGPTL4/8 cleavage and increased LPL activity. Restoration of LPL activity in the presence of ANGPTL4/8 was also achieved with plasmin but was blocked when catalytically inactive plasminogen (S760A) was added to tPA or when plasminogen activator inhibitor-1 was added to tPA + plasminogen, indicating that conversion of plasminogen to plasmin was essential. Together, these results suggest that LPL-bound ANGPTL4/8 mimics fibrin to recruit tPA and plasminogen to generate plasmin, which then cleaves ANGPTL4/8, enabling LPL activity to be increased. Our observations thus reveal a unique link between the ANGPTL4/8 complex and plasmin generation.

As occupational rehabilitation services are part of the public medical and health services in Hong Kong, work-injured workers are treated along with other patients and are not considered a high priority for occupational rehabilitation services. The idea of a work trial arrangement in the private market occurred to meet the need for a more coordinated occupational rehabilitation practice. However, there is no clear service standard in private occupational rehabilitation services nor concrete suggestions on how to offer rehabilitation plans to injured workers. Electronic Health Records (EHRs) data can provide a foundation for developing a model to improve this situation. This project aims at using a machine-learning-based approach to enhance the traditional prediction of disability duration and rehabilitation plans for work-related injury and illness. To help patients and therapists to understand the machine learning result, we also developed an interactive dashboard to visualize machine learning results. The outcome is promising. Using the variational autoencoder, our system performed better in predicting disability duration. We have around 30% improvement compared with the human prediction error. We also proposed further development to construct a better system to manage the work injury case.

To investigate the incidence of hepatocellular carcinoma (HCC) in Chengdu, identify the risk factors for the development of HCC in Chengdu and provide a reference for the prevention of HCC.The study population was recruited from Chengdu, Sichuan Province, China. The study group recruited volunteers in Chengdu from 2007 to 2012, conducted a baseline survey, and subsequently conducted long-term follow-up until December 31, 2019. A total of 22,525 study subjects were enrolled, excluding those who reported a previous history of liver disease, malignancy, and HCC within three months of enrollment. Cox proportional risk regression models were used to screen and determine the various risk factors and their hazard ratios (HR) for HCC in Chengdu, as well as to determine whether the association between other risk factors and HCC was modified by gender.The study population had a median follow-up of 5.35 years, and a total of 142 people developed HCC, with an incidence rate of 0.71%. Analysis of the multifactorial Cox proportional risk regression model showed that age (age 10 years for 1 group, HR= 1.98, 95% CI: 1.86-2.11, p0.001), current smoking (HR= 1.25, 95% CI: 1.07-1.31, p=0.031), weekly consumption of pickled vegetables (HR= 1.70, 95% CI: 1.49-1.81, p=0.003) and consumption of pickled vegetables daily (HR= 1.36, 95% CI: 1.21-1.42, p=0.021) were risk factors for HCC, and women (HR= 0.39, 95% CI: 0.28-0.55, p=0.002) and the use of air conditioning (10 years for 1 group, HR= 0.79, 95% CI: 0.68-0.83, p=0.002) were protective factors against HCC. Further analysis revealed that the association between length of time using air conditioning and HCC was heterogeneous among men and women (p=0.007) and that there was an interaction between sex and use of air conditioning in the association with HCC development (p0.001).The Chengdu population has a high incidence of HCC and numerous risk factors for HCC. There is a synergistic interaction between sex and length of time using air conditioning in their role in the development of HCC.

An absolute measurement of the Λ_{c}^{+} lifetime is reported using Λ_{c}^{+}→pK^{-}π^{+} decays in events reconstructed from data collected by the Belle II experiment at the SuperKEKB asymmetric-energy electron-positron collider. The total integrated luminosity of the data sample, which was collected at center-of-mass energies at or near the ϒ(4S) resonance, is 207.2 fb^{-1}. The result, τ(Λ_{c}^{+})=203.20±0.89±0.77 fs, where the first uncertainty is statistical and the second systematic, is the most precise measurement to date and is consistent with previous determinations.